Process of preparing alpha-acetopyridines



Patented Jan. '6, 1953 PROCESS OF PREPARING a-ACETO- PYRIDINES StanleyH. Hesse, Phillipsburg, N. J assignor to General Aniline & FilmCorporation, New York, N. Y., a corporation of Delaware No Drawing.Application June 1, 1951, Serial No. 229,519

6 Claims. (01. 2s0 297) This invention relates to a-a-cetopyridines andparticularly to an improved process of preparing the same.

It is known that a-acetopyridine can be synthesized by several methods.The compound can be prepared from calcium picolinate by fusion withcalcium acetate. It has been prepared from5-2pyridyl-fi-oxo-ethylpropionate by acid hydrolysis anddecarboXyla-tion. The widely acceptable method to date has been itspreparation from ethyl picolinoyl acetate, which is prepared by athree-step reaction from a-picoline. All of these methods are involved,time consuming, and use relatively expensive and sometimes unavailablechemicals.

I have found that a-acetopyridines can be readily prepared in a veryeconomical manner by utilizing as the starting materials commerciallyavailable a-vinylpyridine and nuclea substituted a-vinylpyridines whichare converted to the a.- halo-methyl-Z-pyridyl lower alkyl ethers,followed by removal of hydrogen halide and bydrolysis to the desireda-acetopyridine.

Accordingly, it is an object of the present invention to provide animproved method for the preparation of such a-acetopyr'idines.

Other objects and advantages will become ap parent from the followingdescription.

The foregoing objects are readily accomplished by reactinga-vinylpyridine or nuclear substituted a-vinylpyridine with a halogen,such as bromine or chlorine and a lower alkyl alcohol, either in thepresence or absence of an acid binding agent at a temperature below 20C., i. e., ranging from -5 to 15 0., preferably at 0 to 10 0., for atime sufiicient to permit the equivalent weight of chlorine or bromineto be absorbed by the avinylpyridine. During this initial reaction, alower alkoxy group and either bromine or chlorine are simultaneouslyintroduced to the vinyl group of the a-vinylpyridine. A heavyprecipitate of the insoluble inorganic salt is formed early in thereaction. The halogen, i. e., chlorine or bromine, is passed into thereaction until the required weight of halogen has been absorbed asindicated by the increase in weight. As this point, the reaction isusually acidic in character and a positive test for hypochlorite ion isobtained if the addition of halogen is continued. This is to be avoided.At the end of the addition of either .bromine or chlorine, theprecipitated inorganic salt may be removed by filtration, but this isnot absolutely necessary. The intermediate is the (ll-loweralkoxy-fi-halo) 2 ethylpyridine which may be isolated if desired at thispoint. This intermediate readily loses the elements of hydrogen halideby heating an alcoholic solution with an excess of alkali, preferablysodium or potassium hydroxide. The addition of water and acidificationwith dilute aqueous acid hydrolyzes the intermediate vinyl ether to givethe desired '0.-

acetopyridine which is characterized by the following general formula;

wherein R represents hydrogen, a lower alkyl group, e. g., methyl,ethyl, propyl, isopropyl, butyl, and the like.

As examples of suitable a-vinylpyridines and nuclea substituteda-vinylpyridines which may bereacted with a lower alcohol and witheither chlorine or bromine according to the foregoing procedure, thefollowing are illustrative:

z-vinylpyridine 3-vinylpyridine 4-vinylpyri-dine 5-ethyl-2-vinylpyridineZ-methyl-S-vinylpyridine 2-propyl-5-vinylpyridine2-methyl-6-vinylp-yridine 2-butyl-6-vinylpyridine2,4-dimethyl-fi-vinylpyridine 2,4-diethyl-fi-vinylpyridine Whenutilizing gaseous chlorine, the chlorination of the c-vinylpyridine ornuclear substituted a-vinylpyridine, which hereinafter and in the claimswill be referred to merely as a-vinylpyridine, is effectuated, aspointed out above, either in the presence or absence of an alkalinemedium, such as an acid binding agent, such as hydroxides or carbonatesof alkali metals-or alkaline earth metals, heterocyclic nitrogenousbases, such as pyridine, dimethylpyridine, ethylpyridine,ethylmethylpyridine, trimethylpyridine, quinoline and the like,trialkylamine, such as trimethylamine, triethylamine, tributylamine,etc.,

alkoxides of alkali metals, such as sodium alkoxides, and alkali metalsalts of lower aliphatic acids, such as sodium acetate. It is preferableto carry out the addition of halogen at a lower temperature, i. e., 5 to5 C. The alkaline reagent is preferably used in an amount in excess tothe equimolecular amount of the a-vinylpyridine and may be added all atonce, portionwise, or by gradual addition. Throughout the main part ofthe chlorination, the pH of the reaction mixture remains above 10, and aweak hypochlorite test is obtained by acidified potassium iodidesolution. The addition of chlorine is discontinued when the pH reaches 6to 7. At this point, chlorination does not increase the yield of thedesired product and stronger hypochlorite tests are obtained.

After chlorination is complete, the white precipitate is filtered offand washed with a lower alcohol, preferably a cheaper alcohol, such asmethanol. If the filtrate should be alkaline, i. e., between a pH of 7to 8, it is brought back to a pH of 5 to 6 with a small amount of aconcentrated mineral acid, preferably hydrochloric.

The lower alcohol utilized in the reaction is stripped off through acolumn at atmospheric or reduced pressure until two layers are formed atwhich time most of the alcohol is removed.

Bromination is carried out in a manner similar to that employed forchlorination. Bromine is added dropwise to the a-vinylpyridine loweralcohol mixture either in the presence or absence of an alkali, i. e.,acid condensing agent until the required weight has been absorbedcorresponding to the formation of the bromoalkis then dehydrochlorinatedor dehydrobrominated by heating, preferably under reflux, with an.alcoholic solution with sodium or potassium hydroxide to yield the loweralkoxy-2-ethylpyridine which is readily hydrolyzed to thea-acetopyridine by heating with mineral acid or by heating in aceticacid containing water with or without a small amount of another acid,such as hydrochloric, sulfuric, phosphoric, hydrobromic, and the like.Any of'these' acids or mixtures thereof may be. added prior to or.during the hydrolysis reaction and prior to the bromination orchlorination reaction.

The following examples are illustrative of the method of preparing thea-acetopyridines and are not to be construed as being limitative.

EXAMPLE I Z-acetopyrz'dine In a 250 ml., 3-necked flask equipped with astirrer, thermometer, and gas inlet and outlet tube were placed 21 grams(0.2 mol) of 2-vinylpyridine, 200 m1. of methanol, and 9.6 grams (0.24mol) of sodium hydroxide. The solution was cooled to to C. by an icebath and chloline gas introduced over a period of '70 minutes untilthere was a gain in weight of 14.5 grams. The pH of the reaction mixturewas 13-14 at this time. Introductionof chlorine for another odor.

minute caused the pH to suddenly drop to slightly below '7. The saltformed by the reaction was filtered off and washed with methanol. Thefiltrate consisting of 190 ml. contained the (a.- methoxy, p-chloro)2-ethylpyridine. This was divided into two equal parts. One portion washeated on a steam bath to remove the methanol, and then drowned in waterto yield the impure intermediate as an oil.

The other portion was placed in a 250 ml., 3- necked flask equipped witha stirrer, thermometer and reflux condenser and heated to reflux aftermaking it alkaline with the addition of 9.6 grams (0.24 mol) of sodiumhydroxide. Salt began to separate at once, but the heating at reflux wascontinued for two hours. When cool, the reaction mixture was filteredfrom the salt and the filtrate acidified with ml. of concentratedhydrochloric acid in 225 ml. of water which was sufficient to make itacid to Congo paper. The acid solution was heated on a steam bath for anhour and then allowed to cool. It was made alkaline to phenolphthaleinwith sodium hydroxide and then extracted with ether. Evaporation of theether left a brown oil as a residue. A sample of this oil was treatedwith phenyl hydrazine in ethanol solution to yield a yellow precipitatewhich melted at l54-155 C. Recrystallization from ethanol raised themelting point to 154.5 to C. The literature value of the melting pointof the phenyl hydrazine of a-acetopyridine was 155 C. Another sample ofthe ether residue formed a p-nitro phenyl hydrazone which melted at262-263 C. after crystallization from acetic acid.

EXAMPLE II Z-acetopyridine In a 3-liter, 3-necked flask equipped with astirrer, thermometer and gas inlet and outlet tube there were placed 210grams (2 mols) of 2-vinylpyridine, 2000 ml. of methanol, and 96 grams(2.4 mols) of sodium hydroxide. When solution was complete, it wascooled to 3 C. and chlorine introduced in 1% hours. When the reactionmixture was acid to pH paper, 192 grams (4.8 mols) of sodium hydroxidewere added and the reaction mixture slowly heated to reflux for 2 hours.It was then cooled and 550 ml. of concentrated hydrochloric acid wereadded to make the reaction mixture acid to Congo paper. The acid solution was heated to reflux, and the methanol allowed to distill over.1850 ml. of methanol were collected. The concentrated reaction productwas made alkaline by the addition of 300 ml. of 40% sodium hydroxide.The reaction mixture now contained a brown oil anda voluminousprecipitate of salt. Sufficient water was added to dissolve the salt andthe oil was separated ina separatory funnel. About 200 ml. of benzeneWere added to the oil and the benzene solution refluxed until all waterwas removed. The benzene was then distilled off and the residue wasfractionally distilled at 58 mm. The fraction boiling at 110.0 to 110.5"C. was collected and weighed 25.5 (10.5% of the theoretical yield). Itwas slightly yellow in color and had a fragrant The refractive index at25 C. was 1.5172.

Analysis for C'7H7NO1 Per cent C theory 69.40-found 70.68 Per cent Htheory 5.83-found 6.44 Per cent N theory 11.5'7-found 11.11

5 EXAMPLE III 5 -ethyZ-2-acetopyridine The process of Example I wasrepeated with the exception that 26.6 parts of 5-ethyl-2-vinylpyridinewere used instead of 21 parts of 2-vinylpyridine. The yield of5-ethy1-2-acetopyridine was excellent.

EXAMPLE IV 5-methyZ-2-acetopyridine The process of Example II wasrepeated with the exception that 238 parts of 2-methyl-5- vinylpyridinewere used instead of 210 parts of 2-vinylpyridine.

EXAMPLE V (i-methyZ-Z-acetopyridine The process of Example II wasrepeated with the exception that 238 parts of 2-methyl-6-vinylpyridinewere used instead of 210 parts of 2- vinylpyridine. The yield of6-methyl-2-acetopyridine was good, although the percentage of conversionwas slightly 10w.

EXAMPLE VI 4,6-dimethyZ-2-acet0pyridine The process of Example II wasrepeated with the exception that 266 parts of 2,4-dimethyl-6-vinylpyridine were used instead of 210 parts of 2- vinylpyridine. Theyield of 4,6-dimethyl-2- acetopyridine was good and the percentage ofconversion was satisfactory.

6 I claim: 1. The process of preparing a-acetopyridines characterized bythe following formula:

wherein R represents a member selected from the class consisting ofhydrogen and lower alkyl, which comprises reacting a-vinylpyridine witha lower alcohol and a halogen selected from the class consisting ofbromine and chlorine at a temperature below 20 C. to yield (a-loweralkoxyr ,9 halo)-2-ethy1pyridine, dehydrohalogenating the (a-loweralkoxy-B-halo)-2-ethylpyridine by heating in the presence of alcoholicalkali, by separating the a-alkoxy-2-ethy1pyridine, and hydrolyzing itin Water to a-acetopyridine.

2. Proces according to claim 1, wherein a-vinylpyridine isZ-Vinylpyridine.

3. Process according to claim 1, wherein a-vinylpyridine is5-ethyl-2-vinylpyridine.

4. Process according to claim 1, wherein a-vinylpyridine is2-methy1-5-vinylpyri-dine.

5. Process according to claim 1, wherein a-vinylpyridine is2-methy1-6-viny1pyridine.

6. Process according to claim 1, wherein the a-vinylpyridine is2,4-dimethyl-6-vinylpyridine.

STANLEY H. HESSE.

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1. THE PROCESS OF PREPARING A-ACETOPYRIDINES CHARACTERIZED BY THEFOLLOWING FORMULA: